Applicators for microneedles

ABSTRACT

An applicator for a microprojection array is described. In one embodiment, the applicator comprises an energy-storing element. Application of force causes the compressed energy-storing element to extend or transition from first and second configurations, releasing stored energy to deploy a holding member in the application which is configured to hold an array of microprojections. In another embodiment, the applicator comprises an energy storing element with two stable configurations, a first stable configuration and second stable configuration. Application of force causes the energy-storing element to transition from the higher energy first stable configuration to the lower energy second stable configuration, releasing the difference in energies of the two states to deploy a holding member in the application which is configured to hold an array of microprojections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/100,924, filed May 4, 2011, now U.S. Pat. No. 9,687,640, which claimsthe benefit of U.S. Provisional Application No. 61/331,175, filed May 4,2010, each of which is incorporated by reference herein.

REFERENCE TO SEQUENCE LISTING

A Sequence Listing is being submitted electronically via EFS in the formof a text file, created Jun. 22, 2017, and named0915000695SequenceListing.txt (790 bytes), the contents of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The subject matter described herein relates generally to drug deliveryusing microneedles or other microprojections, and more specifically toapplicators for applying an array of microprojections to the stratumcorneum.

BACKGROUND

Arrays of microneedles were proposed as a way of administering drugsthrough the skin in the 1970s, for example in expired U.S. Pat. No.3,964,482. Microneedle arrays can facilitate the passage of drugsthrough human skin and other biological membranes in circumstances whereordinary transdermal administration is inadequate. Microneedle arrayscan also be used to sample fluids found in the vicinity of a biologicalmembrane such as interstitial fluid, which is then tested for thepresence of biomarkers.

In recent years it has become more feasible to manufacture microneedlearrays in a way that makes their widespread use financially feasible.U.S. Pat. No. 6,451,240 discloses some methods of manufacturingmicroneedle arrays. If the arrays are sufficiently inexpensive, forexample, they may be marketed as disposable devices. A disposable devicemay be preferable to a reusable one in order to avoid the question ofthe integrity of the device being compromised by previous use and toavoid the potential need of resterilizing the device after each use.

In addition to cost, integrity and sterility, a further issue withmicroneedle arrays is bioavailability of the active agent. Anintravenous injection delivers a precise quantity of an active agent tothe circulation. A subcutaneous or intramuscular injection delivers aprecise quantity of an active agent into the tissue, but the quantity ofactive agent delivered to the circulation and the rate at which activeingredient is delivered are affected by the type of surrounding tissue,circulation, and possibly other factors. When a drug is deliveredorally, the resulting blood levels may exhibit substantial variationamong patients due to metabolism and other factors, but minimaltherapeutic levels can be assured for most patients, for example,because the rate of metabolism has an upper limit and because there islong experience with the absorption of many drugs from oralformulations. When a drug is delivered to unmodified skin by aconventional transdermal patch, the bypassing of the hepatic circulationmay lessen the effect of liver metabolism on bioavailability. On theother hand, with a conventional transdermal patch, differences in skinpermeability are an additional factor leading to differences inbioavailability.

Microneedles manipulate the permeability of the skin with respect to theactive agent. Variability in the permeability enhancement created bydifferent applications of the microneedles will result in variations inthe rate of transfer through the skin, the amount transferred throughthe skin and the bioavailability. Variability of skin permeabilityenhancement on the application of a microneedle array can result fromapplication on different patients. Particular concern exists, of course,if the enhancement is small in particular patient populations so thatthe administration of the drug will not produce a therapeuticallyeffective dosing (e.g., adequate blood levels) in those populations.Concern may arise also if the enhancement is sometimes undesirably smallin a patient, even if at other times the enhancement is as expected inthat patient, depending on details of how and where the microneedlearray is applied.

A typical microneedle array comprises microneedles projecting from abase of a particular thickness, which may be of any shape, for examplesquare, rectangular, triangular, or circular. The microneedlesthemselves may have a variety of shapes. While an array could be pressedby hand into skin, it has also been proposed to use a variety of devicesto hold the microneedle array as it is being applied or to facilitate inone way or another the process of microneedle array application to theskin or other biological membrane. Such devices may broadly be referredto as “applicators.” Applicators may for example reduce the variationsin force, velocity, and skin tension that occur when a microneedle arrayis pressed by hand into the skin. Variations in force, velocity and skintension can result in variations in permeability enhancement.

In some applications of microneedle arrays, they may be applied to theskin or other biological membrane in order to form microchannels andthen are more or less immediately withdrawn. In other applications themicroneedle array may be held in place for a longer period of time. Thedesign of the applicator may naturally be influenced by how long themicroneedles are expected to stay in place.

Applicators for microneedles comprising components which have two stablestates have been described in U.S. Published Patent Application No.2008/0183144. The existence of two stable states is a feature generallydesired in an applicator because the energy difference between the twostable states can allow each use of the applicator to employ a fixedamount of energy in order to cause penetration, improvingreproducibility. However, a limitation of this earlier approach is thatthe energy delivered to the microstructure array is both limited andvariable. The earlier approach was dependent on the input of the userfor both energy and velocity, and variation in application technique hada significant effect on the ability of the device to enhance thepermeability of the skin.

In some other prior art applicator designs, the energy storage element,such as a spring or elastic element, may exert forces on one or morecomponents of the applicators, leading to dimensional distortion andcreep over an extended period of time. These effects are undesirable asthey lead to variations in the applicator geometry and a loss in thestored elastic energy over time. Therefore, there is a need for anapplicator which has energy storage elements that do not exert forces onone or more components of the applicator.

In the use of microneedle arrays, particularly when the arrays are keptin place for a prolonged period of time, devices to transport the drugsubstance to the skin may be employed. A very simple such device may,for example, comprise a reservoir for liquid or solid drug substancewhich is kept in contact with the base, with the liquid drug substanceflowing through small apertures in the base or by diffusion when soliddrug substance is used. Another device suitable for delivering the drugsubstance to skin is described in U.S. Published Patent Application No.2005/0094526. Rotary applicators have been disclosed in U.S. PublishedPatent Application No. 2004/0087992. There is some disclosure relatingto applicators, for example, in U.S. Pat. Nos. 6,537,242, 6,743,211 and7,087,035.

There is a need in the art for applicators and related devices suitablefor use with microneedle arrays, for example, in order to assist inmaking the process of drug delivery more user friendly and uniformacross patients and for different applications to the same patient.

BRIEF SUMMARY

In one aspect, an applicator for a microprojection array is provided.The applicator comprises an energy-storing element which has a firststable configuration and second stable configuration, whereinapplication of force can cause the energy-storing element to transitionfrom the first stable configuration to the second stable configuration,and wherein the force necessary for the energy storing element totransition from the first stable configuration to the second stableconfiguration is lower than the force necessary for the element totransition from the second stable configuration to the first stableconfiguration. The applicator also comprises an actuating member thatcan convey external force to the energy-storing element, amicroprojection-holding member connected to the actuating member andwhich is acted on by the energy-storing element when it transitions fromthe first stable configuration to the second stable configuration, anouter cover with an opening into which the actuating member fitsslidably, and a skin-contacting member comprising a portion which canlie flat against skin, wherein the skin-contacting member fits the outercover and contacts the energy-storing element when it is in its firstconfiguration.

In one embodiment, the energy-storing element has an axis of symmetryand n-fold rotational symmetry for some integer n. In anotherembodiment, application of force to the energy-storing element in adirection of its axis of symmetry causes it to transition from the firststable configuration to the second stable configuration.

In another embodiment, an applicator for a microprojection arraycomprises a housing having a surface with an elongated opening havingplatforms on opposite sides of the opening. An actuation membercomprising a surface upon which a microprojection array can be attached,a generally washer-shaped surface on which an energy-storage member canbe placed, and a surface capable of mating with the platforms on theopening of the housing and capable of fitting through the opening isincluded. An energy-storage member is situated between the actuationmember and the housing, and a skin-contacting area which is generallywasher-shaped is connected to the housing. In one embodiment, when theactuation member is mated with the platforms on the opening, theenergy-storage member is compressed, and when the actuation member ismoved within the opening so that it no longer mates with the platforms,the energy-storage member is free to expand and in so doing moves theactuation member.

In one embodiment, the energy-storage member is in the form of a wavespring. In other embodiments, the energy storage member has an n-foldrotational axis of symmetry of between about 3-22, more preferably 3-18or 3-9, and still more preferably between 3-6.

In another embodiment, the actuator member moves within the outer coverbetween a first position and a second position, wherein in its firstposition the actuator member extends outwardly from and beyond an uppersurface of the outer cover.

In another embodiment, the actuator member moves within the outer coverbetween a first position and a second position, wherein in its firstposition the actuator member is recessed within the outer cover.

In yet another embodiment, the microprojection array is attached to themicroprojection-holding member, the microprojection array comprises abase, and the level of the microprojection array's base is below askin-contacting surface of the skin-contacting member followingactuation of the actuating member.

In still another embodiment, the level of the microprojection array'sbase below the skin-contacting surface of the skin-contacting member isbetween about 0.001 inches to about 0.200 inches, more preferablybetween about 0.001 inches to about 0.125 inches, still more preferablyfrom about 0.030 inches to about 0.090 inches.

In another embodiment, the energy-storing element is in mechanicalcoupling relationship with the microprojection-holding member when theenergy-storing element is in its first stable configuration.

In another aspect, an applicator for a microprojection array isprovided. The applicator comprises (a) a housing having a surface withan elongated opening having platforms on opposite sides of the opening;(b) an actuation member comprising a surface upon which amicroprojection array can be attached, a generally washer-shaped surfaceon which an energy-storage member can be placed, and a surface capableof mating with the platforms on the opening of the housing and capableof fitting through the opening; (c) an energy-storage member situatedbetween the actuation member and the housing; and (d) a skin-contactingarea which is generally washer-shaped connected to the housing. When theactuation member is mated with the platforms on the opening, theenergy-storage member has a first force of stored energy, and when theactuation member is moved within the opening so that it no longer mateswith the platforms, the energy-storage member releases its stored energyand in so doing moves the actuation member.

In one embodiment, the energy-storage member when mated with theplatforms on the opening has a first force of stored energy by virtue ofits being compressed.

In yet another aspect, an applicator is provided. The applicatorcomprises (a) a housing having a first member with a central opening anda second member having a skin contacting surface; (b) an actuationmember disposed in the central opening and comprising a surface uponwhich a microprojection array can be attached and a groove extendingcircumferentially; and (c) an energy-storage member having an inner edgeand an outer edge, and situated within the housing initially in a firststable configuration such that the inner edge is disposed in the grooveand its outer edge is in contact with the second member. Application offorce to the actuation member moves the energy-storage member from itsfirst stable configuration to a second stable configuration wherein theouter edge is no longer in contact with the second member.

In one embodiment, the outer edge of the energy storage member in itssecond stable configuration is in contact with the first member.

In another embodiment, a microprojection array holder engages theactuation member, the engagement of the actuation member and themicroprojection array holder defining the groove.

In still another embodiment, the energy-storage member has an axis ofsymmetry and n-fold rotational symmetry for some integer n, whereinapplication of force in a direction of the axis of symmetry causes theenergy-storing element to transition from the first stable configurationto the second stable configuration, and wherein the force necessary forthe energy storing element to transition from the first stableconfiguration to the second stable configuration is lower than the forcenecessary for the element to transition from the second stableconfiguration to the first stable configuration.

In yet another embodiment, the energy-storing element is of generallyfrustoconical shape with slots from the top of the frustum, from thebottom of the frustum, or from both.

In another aspect, any of the applicator embodiments described hereinfurther comprises a safety mechanism to prevent movement of theactuation member in a direction that deploys the microprojection array.

In one embodiment, the safety mechanism comprises a protective cap overthe applicator housing. In another embodiment, the safety mechanismcomprises a pin movably inserted into the actuation member on anapplicator.

In another aspect, a device comprising an applicator in accord with anyof the aspects and embodiments described herein and a microprojectionarray comprising an active agent is provided.

In another aspect, a method for applying a microprojection array to abiological barrier is provided. The method comprises providing anapplicator as described herein, the applicator including or capable ofincluding a microprojection array. The applicator is contacted with thebiological barrier, and an actuating member on the applicator isactivated, to initiate movement of the energy-storage member from itsfirst stable configuration to its second stable configuration. Movementof the energy-storage member induces movement of the microprojectionarray, directly or indirectly, causing it to forcibly contact thebiological barrier. In embodiments where the microprojection arraycomprises a therapeutic or prophylactic agent, the method achievesadministration of the agent to a subject.

Additional embodiments of the present method, microprojection array,kit, and the like will be apparent from the following description,drawings, examples, and claims. As can be appreciated from the foregoingand following description, each and every feature described herein, andeach and every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment of the present invention. Additionalaspects and advantages of the present invention are set forth in thefollowing description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B are views of an applicator as described herein, theapplicator shown in perspective views (FIG. 1A), a sectional view (FIG.1B) and an exploded view (FIG. 1C).

FIGS. 1D-1E show the applicator of FIGS. 1A-1C in perspective view (FIG.1D) and in a cross-sectional view (FIG. 1E) after actuation of itsactuating member.

FIGS. 1F-1T are perspective views of embodiments of energy-storageelements for use in an applicator as described herein.

FIGS. 1U-1V illustrate movement of an energy-storage element between itsfirst stable configuration and its second stable configuration.

FIG. 2A depicts schematically, with certain dimensions exaggerated forclarity, an applicator.

FIG. 2B depicts schematically, with certain dimensions exaggerated forclarity, one quarter of the push member of the applicator of FIG. 2A.

FIGS. 3A-3B depict schematically another embodiment of an applicator,where in FIG. 3A a schematic cross-section of one half of the applicatoris shown, and in FIG. 3B a perspective view of a particular component isshown.

FIG. 4A shows an exploded view of another embodiment of an applicator.FIG. 4B shows a perspective view of the same applicator.

FIG. 5 depicts an alternative outer member for the applicator of FIGS.4A-4B.

FIGS. 6A-6B illustrate a cantilevered pin safety mechanism to preventunintentional deployment of an activator.

FIGS. 7A-7B illustrate another embodiment of a safety mechanism toprevent unintentional deployment of an activator.

FIGS. 8A-8B illustrate an example of tab safety mechanisms to avoidaccidental actuation of an actuation member in an applicator.

FIGS. 9A-9C illustrate another embodiment of a safety mechanism, where aprotective cap is shown in a closed position (FIG. 9A) and in an openposition (FIG. 9B), and disposed in place on an applicator (FIG. 9C).

FIGS. 10A-10B illustrate another embodiment of a cap type safetymechanism.

FIGS. 11A-11B are perspective views of an applicator according to yetanother embodiment, wherein FIG. 11A depicts the applicator in aconfiguration prior to deployment or actuation by a user, and FIG. 11Bdepicts the same applicator after deployment or actuation by a user.

FIGS. 12A-12B are cross-sectional side views of a first embodiment ofinternal components of an applicator according to the applicator ofFIGS. 11A-11B, wherein FIG. 12A depicts the applicator in aconfiguration prior to deployment or actuation by a user, and FIG. 12Bdepicts the same applicator after deployment or actuation by a user.

FIGS. 13A-13B are cross-sectional side views of a second embodiment ofinternal components of an applicator according to the applicator ofFIGS. 11A-11B, wherein FIG. 13A depicts the applicator in aconfiguration prior to deployment or actuation by a user, and FIG. 13Bdepicts the same applicator after deployment or actuation by a user.

DETAILED DESCRIPTION

Before describing the present subject matter in detail, it is to beunderstood that this invention is not limited to specific materials ordevice structures, as such may vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include both singular and plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an active ingredient” includes a plurality of activeingredients as well as a single active ingredient, reference to “atemperature” includes a plurality of temperatures as well as singletemperature, and the like.

For information regarding words which have multiple meanings, referenceis made to The Oxford English Dictionary (2d ed. 1989) and theMcGraw-Hill Dictionary of Scientific and Technical Terms (6th ed. 2002),which are incorporated by reference herein. The inclusion of thesereferences is not intended to imply that every definition in them isnecessarily applicable here, as persons of skill in the art would oftensee that a particular definition is not in fact applicable in thepresent context.

In this application reference is often made for convenience to “skin” asthe biological membrane which the microneedles penetrate. It will beunderstood by persons of skill in the art that in most or all instancesthe same inventive principles apply to the use of microneedles topenetrate other biological membranes such as, for example, those whichline the interior of the mouth or biological membranes which are exposedduring surgery.

In this application reference is also made to “microneedles” as the typeof microprotrusion or microprojection which is being employed. It willbe understood by persons of skill in the art that in many cases the sameinventive principles apply to the use of other microprotrusions ormicroprojections to penetrate skin or other biological membranes. Othermicroprotrusions or microprojections may include, for example,microblades as described in U.S. Pat. No. 6,219,574 and Canadian patentapplication no. 2,226,718, and edged microneedles as described in U.S.Pat. No. 6,652,478.

In discussing the applicators of this invention, the term “downward” issometimes used to describe the direction in which microprotrusions arepressed into skin, and “upward” to describe the opposite direction.However, those of skill in the art will understand that the applicatorscan be used where the microprotrusions are pressed into skin at an angleto the direction of the earth's gravity, or even in a direction contraryto that of the earth's gravity. In many applicators of the invention,the energy for pressing the microprotrusions is provided primarily by anenergy-storage member and so efficiency is not much affected by theorientation of the skin relative to the earth's gravity.

The sizes of the microneedles and other microprotrusions for use withthe applicators described herein will be a function of the manufacturingtechnology and of the precise intended application (e.g., the activeagent to be delivered, whether it is contained in the microprojections,etc.). In general, however, microneedles and other microprotrusions usedin practice may be expected to have a length of about 20 to about 1000microns, more preferably from about 50 to about 750 microns and mostpreferably from about 100 to about 500 microns. Often it will be desiredthat the microprotrusions will be long enough to penetrate through thestratum corneum layer of skin at some suitable point of application onthe human body, for example the thigh, hip, arm, or torso.

The term “microneedle array” for purposes herein is intended to denote atwo-dimensional or a three-dimensional arrangement of microneedles. Thearrangement may be regular according to a repeating geometric pattern orit may be irregular. Similarly, “microprojection array” denotes atwo-dimensional or three-dimensional arrangement of microprojections.

In a first aspect, an applicator for microprojection arrays is providedin which the velocity at the time of microprojection array contact withskin is controlled within a predetermined range. The applicator operateswhen an actuating element is pressed with a force which is above athreshold. The velocity of contact is substantially independent of theprecise force employed to press the actuating element. The applicatorcomprises an energy-storing element.

In a further aspect, a method for inserting microprojections in an arrayof microprojections into skin or another biological barrier is provided.The method comprises placing an applicator in contact with the barrierinto which the array is to be inserted and operating an actuatingelement which forms part of the applicator with a force which lies abovea predetermined threshold. The velocity of the microprojection array andthe energy per microstructure at the time of contact with skin need tobe above a threshold and may be controlled within a predetermined range.

Applicators contemplated herein will commonly have two states orconfigurations. In the first state or configuration, the applicator hasthe microprojection array recessed. This is expected to be the state ofthe applicator following manufacturing and during shipping and storage.In the second state or configuration, which is arrived at by pressing orotherwise operating the actuating element, the microprojection arrayprojects modestly outward from the applicator.

The velocity of the microprojection array at the time of contact withskin may be adjusted, for example, by varying the amount of storedenergy in the energy-storing element. This is done, for example, bycontrolling the energy-storing element's geometric design and theproperties of the material(s) out of which the energy-storing element ismade. The energy-storing element may have a compressed form in which thedegree of compression (e.g., in one spatial direction) controls theamount of energy stored.

When the energy storing element is stored in compressed form, a varietyof mechanisms external to the element, but forming part of theapplicator, may be employed to release the compression and allow theelement to uncompress and therefore release some or all of its energy.

Alternatively, the energy-storing element may be bistable in that it hastwo stable states in which energy is stored. The two states may havedifferent energies. The amount of stored energy may be, for example, inthe range of about 0.1 J to about 10 J, or in the range of about 0.25 Jto about 1 J. The energy storage element having two bi-stable states ishighly advantageous because in its higher energy state, the energystorage element does not exert any significant forces on the applicatorcomponents, thereby alleviating the problems with dimensional distortionand creep over time. Reducing the dimensional distortion and creep leadto maintaining the same stored elastic energy for an extended period oftime. Maintaining the same stored elastic energy over a period of timeis important for having an extended shelf life of at least preferably 6months, more preferably 12 months, and most preferably 24 months.

The velocity of the microprojection array at the time of contact withthe skin may lie, for example, within the range of 0.1 m/s to 20 m/s, orwithin the range of 0.5 m/s to 10 m/s. In general, the stored energy maybe employed in moving the microprojection array into contact with theskin as well as in overcoming any forces (e.g., from other components ofthe applicator) acting on the microprojection array. In addition, thestored energy may be employed in moving other components which, inaccordance with the design of the applicator, must also move as themicroprojection array moves towards the skin.

The velocity of the microprojection array is preferably reproducible.For example, the standard deviation of the velocity in a number ofapplications carried out with different applicators of the same designor by different persons using the same applicator may be less than about10% of the average velocity, less than about 5%, or less than about 1%.

It may be desired that the applicator comprise one or more componentswhich have rotational symmetry about an axis perpendicular to themicroprojection array. For example, the applicator may comprisecomponents which have n-fold rotational symmetry (symmetry underrotations of 360/n degrees), for some integer n>1, for example n=2, 3,4, 5, or 6. To give an example, the clip depicted in FIG. 3B, acomponent of an applicator described herein, has 3-fold rotationalsymmetry.

It may be desirable that the energy-storing element be in mechanicalcoupling relationship with the microprojection array or a member holdingthe array at all times. An alternative design, however, would allow theenergy-storing element not to be coupled to the microprojection arrayduring the stored state of the applicator but only to come into contactwith the array or a member holding the array during the process ofactuation. Such contact may occur at a nonzero velocity, although it isdesirable that this nonzero velocity be low, for example below about 0.1cm/s, or below about 0.25 cm/s or below about 1 cm/s.

Following contact of the microneedle array with skin or another barrier,there may be a modest bounce of the array against the skin given thatskin has elastic properties. The microneedle array may then settle,pressed by the applicator, into the skin at a level which is modestlybelow the original level of the skin. The force with which themicroprojection array is pressed into the skin may be, for example,between about 0.1 and about 10 N/cm². The level of the microprojectionarray's base below the skin is about 0.001 inches (0.00254 cm) orgreater, and in other embodiments is between about 1/16 inch (0.0625inches or 0.159 cm) and about 3/16 inch (0.188 inches or 0.476 cm), orbetween about 1/16 inch (0.0625 inches or 0.159 cm) to about ⅛ inch(0.125 inches or 0.318 cm).

In a common arrangement where a compressed energy-storage device isemployed, the applicator has a primary member, which is contacted withskin when the applicator is to be used. The microprojection array isattached to a retaining member which holds the energy storage device incompression. The retaining member is held in place by a flexiblemechanism. The actuation mechanism causes the flexible mechanism to bedisplaced or elastically deformed in such a way that the retainingmember ceases to be restrained. The energy-storage device is then freeto expand or to move between first and second configurations, moving theretaining member, and the microprojection array is then displacedtowards the skin.

Turning now to the drawings, FIGS. 1A-1C depict several views onepossible arrangement of an applicator 10. The applicator comprises askin contacting element 12 which has an opening 14 in its center, and,in this embodiment, has complete rotational symmetry. Skin-contactingelement 12 mates with an applicator housing 16 which, in thisembodiment, also has complete rotational symmetry and is manufacturedfrom a rigid material (e.g., a polymeric, filled polymeric, composite,or metal material) which preferably does not visibly flex duringoperation of the device). It will be appreciated that the housing canalso be semi rigid, semi-flexible, or flexible, if desired. Housing 16has an opening 18 at the top, through which an actuating member 20slidingly fits. As seen best in FIG. 1B, connected to a bottom surface22 of actuating member 20 is a holder 24 which holds a microprojectionarray (which is not shown in FIGS. 1A-1C). When bottom surface 22 andthe upper surface of holder 24 are in contact, a groove 26 is definedwhich again has complete rotational symmetry. A bistable energy-storagemember 28 having an approximately frustoconical form has an inner edge30 positioned within groove 26. The energy-storage member of thisembodiment is referred to herein as a “slotted spring”, described infurther detail hereinbelow.

FIGS. 1D-1E illustrate the applicator after actuation of actuatingmember 20. Housing 16 and its lower portion with skin contacting element12 are shown in FIG. 1D, where actuating member 20 is not visiblebecause it has been depressed and is fully retained within the housing.Extending slightly beyond the skin contacting element 12 is the bottomsurface of the actuating member on which an array of microprojections isheld. FIG. 1E is a cross-sectional view taken along line A-A in FIG. 1D,where the actuating member contained within the housing is visible. Alsovisible is the configuration of the slotted spring member 28 where itsinner edge 30 is in a second position relative to it is position priorto actuation, as depicted in FIG. 1B. Specifically, inner edge 30 of theenergy-storage member is at a horizontal plane that approaches orapproximates the horizontal plane of the edge of the slotted springprior to use. This transition and inversion of the spring element aredescribed in more detail below.

The materials from which the applicator components are manufactured canbe selected from a wide variety known to a skilled artisan. For example,a filled polymer material is suitable for manufacture of the outercover, the actuating member and/or the microprojection holding member. Askilled artisan will understand the various material properties to beconsidered when selecting a suitable material for each component part.

FIGS. 1F-1G are perspective views of two different embodiments ofenergy-storage members for use in an applicator as described herein,such as that depicted in FIGS. 1A-1E. Energy-storage member 40 of FIG.1F is substantially in the shape of a washer, and more specificallyapproximately a frustoconical shape. Inner rim 42 of the member andouter rim 44 of the member define a disc region 46. Upper slots, such asupper slots 48, 50, are cut into the disc region. Lower slots, such aslower slots 52, 54, are cut into the disc region from the outer rim 44.The upper and lower slots are offset from one another, so that a lowerslot is positioned between adjacent upper slots, and vice versa. Theslots serve to reduce strain of the material during its movement betweenits first and second stable configurations, as will be described.

FIG. 1G illustrates an alternative embodiment of an energy-storagemember 60. Energy-storage member 60 of FIG. 1G is substantially in theshape of a washer, and more specifically a frustoconical shape. Innerrim 62 of the member and outer rim 64 of the member define a disc region66. A plurality of slots, such as slots 68, 70, are cut into the discregion. The slots serve to reduce strain of the material during itsmovement between its first and second stable configurations, as will bedescribed.

The energy-storage members of the present applicator are movable betweenfirst and second stable configurations. In the first stableconfiguration, the inner edge (or rim) of the energy-storage member liesin a first horizontal plane 72 and the outer edge (or rim) of theenergy-storage member lies in a second horizontal plane 74 that is lowerthan the first horizontal plane, as depicted in FIGS. 1U-1V. Applicationof force to the energy-storage member causes movement to a second stableconfiguration, where the inner edge of the energy-storage memberapproaches the second horizontal plane and the outer edge of theenergy-storage member approaches the first horizontal plane. In a sense,the relative positions of the inner rim and outer rim invert as themember transitions from a first to a second stable configuration, andback. In one embodiment, the force for movement from the first stableconfiguration to the second stable configuration is less that the forceneeded to move the member from the second stable configuration to thefirst stable configuration. In one embodiment, a force of at least 10%greater, preferably 20% greater, still more preferably 30% greater isneeded to transition the member from its second stable configuration toits first stable configuration.

In a preferred embodiment, the energy-storage member as an axis ofsymmetry with an n-fold rotational symmetry for n, where n is an integerof 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or20. In a preferred embodiment, n is between 3-18, preferably between3-12, still more preferably between 3-9. By way of example, the slottedspring embodiment of FIG. 1G has an axis of symmetry with a 9-foldrotational symmetry. The energy-storage member is stable in both itsfirst and second configurations, wherein stable intends that the memberdoes not transition between first and second configurations except uponapplication of external force. As noted above, in a preferredembodiment, the force to move from a second configuration to a firstconfiguration is different, e.g., greater, than the force needed to movefrom a first configuration to a second configuration.

A skilled artisan will appreciate the wide variety of energy-storagemembers that would be suitable for use, and examples are illustrated inFIGS. 1H-1T. The embodiments shown, with the exception of FIGS. 1R and1S, have an axis of symmetry. Several of the embodiments have an 9-foldrotational symmetry, for example, the embodiments of FIGS. 1K and 1L.Other embodiments have a 6-fold rotational symmetry, for example, theembodiments of FIGS. 1H, 1J, 1M and 1T. It is to be understood thatother similar shapes, including but not limited to other axisymmetricshapes, may be used to create an energy-storage member with two stableconfigurations. Further, non-symmetric shapes may be used to create anenergy-storage member with two stable configurations. It is also to beunderstood that the presence or absence, size, shape, and configurationof any slots or cutouts in the energy-storage member may be altered toallow the energy-storage member to have two stable configurations. It isalso to be understood that the energy-storage member may comprise aplurality of individual energy-storage members that may or may not beidentical in size, shape, and material. The usage of a plurality ofindividual energy-storage members is useful to allow alteration ofapplicator velocity, energy, activation force, or other performancecharacteristics in ways that may not be achievable with a singleenergy-storage member.

In operation, and with reference again to FIGS. 1A-1E, an applicatorcomprising an energy-storage element is placed in contact with the skinsuch that skin contacting element 12 is directly on the stratum corneumand, optionally, adhered to skin by means of adhesive disposed onelement 12. The energy-storage element is in a first stableconfiguration and is movable to a second stable configuration byapplication of force. Actuating member 20 is pressed downward, in thedirection of arrow 32. This causes actuating member 20 to move downward,engaging inner edge 30 of energy-storage member 28, and applying theforce necessary to move the energy storage member into its second stableconfiguration, wherein the inner edge 30 of the member approaches thehorizontal plane previously defined by the outer edge of the member(e.g., FIGS. 1E-1F). As a result of movement of the energy-storagemember, a microarray in contact with holder 24 comes forcibly intocontact with skin.

The process of inversion of energy storage member may be quite rapid,appearing for example instantaneous to the human eye. It may last, forexample, no more than about 10 ms, no more than about 30 ms, or morethan 100 ms, or no more than ½ second. The shape assumed by energystorage member following inversion may be the reflection of the originalshape in a plane.

The material from which the energy storage member is manufactured isvariable, and a skilled artisan will appreciate that it is selectedbased on the several design considerations, including storage life anddesired application force, which of course will also depend on theconfiguration of the member. Exemplary materials include metals, alloys,plastics, and specific examples include stainless steel andthermoplastics.

FIG. 2A depicts schematically in cross-section, with certain dimensionsexaggerated for emphasis, another embodiment of an applicator, prior toactuation. Applicator 100 comprises three principal members, an actuator102, a housing 104, and a push member 106. Housing 104 comprises adistal edge 108 contoured for contact with skin 110. Housing 104 alsohas at least two projections extending from its inner circumferentialsurface, such as projections 112, 114. In other embodiments, the numberof projections is 3, 4, 5, 6, 7, 8 or more. Each projection mates with amatching projection that extends from push member 106, where FIG. 2shows matching projection 116 mating with projection 112. Collectivelythe projections hold push member 106 and resist the force of a spring118 tending to push the push member 106 down. Member 106 has a planarbase surface 120 onto which a microprojection array 122 is affixable oraffixed.

In order to cause member 106 and the attached microprojection array 122to be driven towards the skin 110, it is necessary to dislodge member106 from the projections such as 112 and 114. In order to do that,actuating member 102 is used. It contains for each of the projectionssuch as 112 and 114 a rod, such as rods 124, 126. The rod by pressingdown on the matching projections causes the projection to flex inwardand to escape from contact with its matching projection, such asmatching projections 112, 114. Having moved past those projections,member 106 is no longer held up by them, and the spring 118 is free torelease its energy in order to move member 106 downward.

The structure of member 106 is further explained by FIG. 2B, whichdepicts schematically one quarter of member 106. It is seen that thisquarter has a base 130, a wall 132, a central column 134 and aprojection 136, which is designed to engage with a projection on theapplicator housing, such as projection 112 seen in FIG. 2A.

In FIGS. 2A-2B as indicated above the dimensions are exaggerated forclarity. In reality the projections on members 104 and 106 might besmaller than depicted in the figures so as not to require so great aflex inwards when the actuation member 102 is pressed down. It would beexpected that all three members 102, 104 and 106 would be composedprimarily of flexible polymers or rigid polymers (including reinforcedpolymers). Possible materials include polycarbonate,polyetheretherketone (PEEK), polyethylene, polypropylene, polyethyleneterephthalate, or other polymeric material. Fillers added to the polymerduring manufacture can include glass fibers, Kevlar fibers, aramidfibers, metal fibers, carbon fibers or other polymeric filler material.These filler materials serve the purpose of carrying additional loadswithin the polymeric matrix such that the mechanical loading experiencedby the polymer in the applicator parts is distributed between thepolymer itself, and the filler. The use of fillers within the polymerreduces the dimensional distortion on the applicator parts if theyexperience any mechanical loading. The polymer and fillers also minimizecreep due to less force experienced by the polymer itself. Reducing thedimensional distortion and creep lead to maintaining the same storedelastic energy for an extended period of time. Maintaining the samestored elastic energy over a period of time is important for having anextended shelf life of preferably at least 6 months, more preferably 12months, and most preferable 24 months. These materials andcharacteristics described herein may also be used for other parts of theapplicator to increase mechanical strength and stability, and reducedimensional distortion and creep.

Many variations on FIG. 2A are possible. For example, the number n ofprojections like 112 and 114 around the inner periphery of member 104could be varied. They would generally be expected to be placed atpositions 360/n degrees apart, but it might be desired to space themmore closely in some instances, for example with four projections at 0degrees, 80 degrees, 180 degrees, and 260 degrees.

The skin-contacting edge 108 of housing 104 could be provided with askirt so that the area which contacts the skin is more extensive. Theskin-contacting edge could be provided with an adhesive, which in turnwould in storage conveniently be covered by an optional release liner.

In the device of FIGS. 2A-2B, the energy needed to actuate is thatrequired to flex inward the projections, such as projections 116 (FIG.2A) or 136 (FIG. 2B) of member 106. This energy depends on their precisedimensions and the material characteristics (e.g., Young's modulus) ofthe material out of which they are made. If this pressure weresufficiently low that inadvertent actuation were a possibility, it mightbe desirable to place some kind of spring or spring-like object betweenthe actuating member and the push member, so that an energy needed todeform this object must be supplied before actuation can occur. The useof such an object allows the user input force to be set at a levelsuitable for the target population without imposing limitations on theenergy stored in the spring used to propel the microneedle array.

In further variants on the design of FIGS. 2A-2B it is possible to usefeatures in addition to or different from the projections to hold a pushmember and spring in place prior to actuation. A design of this type isdepicted in FIGS. 3A-3B.

In FIG. 3A, which is a schematic cross-section, is a member 164 whichmakes contact with skin. Engaged with member 164 is a clip 168, which isdepicted also in perspective in FIG. 3B. Clip 168 has a certain numberof outward projections, such as projection 172. In the embodiment shown,there are three such outward projections. These outward projections maygenerally flex in an approximately radial direction towards the centerof clip 168. These outward projections fit into openings in member 164as shown in FIG. 3A. Underneath member 164 there is a further member 166which holds a microprojection array (which is not shown in the figure).Between members 164 and 166 is a spring 170. Spring 170 serves as anenergy-storing member. It tends to push member 166 downward. However, itis restrained by the projections like 172 of clip 168.

In contact with clip 168 is an actuation member 160. It has openingslike 162, one for each of the outward projections like 172. The lowerportions of these openings like 162 have a surface against which theprojections like 172 press during storage. However, when actuationmember 160 is pushed downwards, eventually the projections like 172 areenabled to flex outwards, releasing member 166 and allowing spring 170to push member 166 downwards towards the skin.

Springs of different kinds (not shown in FIG. 3A) may be used toestablish a minimum force which is necessary to push down member 160 andactuate the applicator. Such springs may, for example, be locatedbetween the upper surface of member 164 and the lower (inner) surface ofactuation member 160.

The clip 168 may be made of metal, while the remainder of the applicatoris made of suitable polymers. By making the clip of metal, the verticalwall of the housing may be made thinner, a thick section on that wallnot being needed to avoid creep. As may be seen from the descriptionabove, the projections 172 in this embodiment extend further outwardthan the position shown in FIG. 3A, so that some force is required topush them in enough to fit the bottom of the opening 162 in housing 160as shown in FIG. 3A.

FIGS. 4A-4B schematically disclose another embodiment of an applicator180, shown fully assembled in FIG. 4A and in exploded view in FIG. 4B.An outer housing 182 is separated by an energy-storage member 183 from amicroprojection-holding member 184 which holds a microprojection array(not shown in the figure). In this embodiment, the energy-storage memberis in the form of a wave spring, as illustrated in FIG. 4B. A wavespring is preferred in some embodiments over other types of compressivesprings due to its small size when compressed, which is of value for adisposable device. It is to be understood that other compressive springsare also suitable and the applicator of this embodiment is not limitedto a wave spring. In storage, microprojection-holding member 184 is heldin place by two platforms in housing 182, such as platform 196, againstwhich a projection member, such as members 185, 187 in member 184,engages. When it is desired to activate the device, a user twists member184 (e.g., with thumb and forefingers gripping projection members 185,187) so that it is no longer over the platforms and restrained by them.When that twisting occurs, member 184 moves downward pressing themicroprojections against the skin.

The applicator of FIGS. 4A-4B is further provided with a set ofcomponents for adapting to skin, in this case an adapter 190, a snapring 186, and an extender 188. This extender has the same function asthe outwardly projecting flange seen in FIG. 3A as part of member 164.In addition, FIG. 4A shows an adhesive 192 and a release liner 194.These kinds of components may also be used in connection with the otherapplicators described herein. The applicator of FIGS. 4A-4B alsoincludes an optional safety feature, in this embodiment in the form of apin 197 that is removably inserted through a cavity in microprojectionholding member 184 prior to use. To enable the applicator for actuation,a user pulls pin 197 from its retaining position as shown in FIG. 4A topermit a user to activate the applicator by the twisting motiondescribed above.

In an alternative embodiment of the applicators of FIGS. 4A-4B, theextender 188 of the applicator may have a frustoconical rather than aflat shape.

In another embodiment of the applicator of FIGS. 4A-4B, the housingmember may be provided with its own outward projection for adaptation toskin, as depicted in FIG. 5. In FIG. 5, housing 220 comprises a basesurface 222 with a projection 224 designed for contact with skin when inuse. An outer portion 226 of the projection 224 has a thickness lessthan an inner portion 228. Reinforcing elements, such as element 230,are provided. Just as in FIGS. 4A-4B, there is an elongated opening 232at the top of housing 220, where the opening comprises two platforms,such as platform 234, against which the microprojection-holding memberpresses when the applicator is in storage.

A feature of merit for applicators is the skin penetration efficiencyachieved with a particular microprojection array. An exemplary test forskin penetration efficiency requires the placement of the microneedlearray upon a test sample of cadaver skin, the insertion of the array theapplicator under testing, and the withdrawal of the array after a periodof time. At that time the percentage of openings in the skin sample thatare deemed to allow adequate transport of material may be taken as afigure of merit. A material that may be used to test adequacy oftransport is India ink. It is desirable that at least about 80%,preferably at least about 90%, and more preferably at least about 95% ofthe openings in the skin allow adequate transport of material.

The applicators described herein above can optionally include a safetymechanism or latch to prevent unintended actuation of the applicator andconsequential deployment of the microneedle array. Various embodimentsof a safety mechanism are now described.

In a first embodiment, a pin or tab is used to prevent accidentalactuation of the applicator. By way of example, FIGS. 6A-6B illustrate acantilevered pin safety mechanism, where a retaining member 300 isdimensioned to snap fit on an applicator housing. Retaining member 300is shown in FIG. 6A positioned on an applicator housing, and is shownalone in an enlarged side view in FIG. 6B. One or more pins, such as pin302, on the retaining member fit within a groove in the actuation memberof an applicator, preventing deployment of the actuation member.Rotation of the retaining member in a clockwise or counterclockwisedirection by pressing on tab 304 releases the pin from the retaininggroove, to allow deployment of the actuation member.

Another example of a pin-type safety mechanism is illustrated in FIGS.7A-7B. Applicator 310 comprises a housing 312 and an actuation member314 movably inserted into an opening in housing 312. A slot 316 isformed in actuation member 314 at a position where the slot is inmovable engagement with a pin 318. When the pin is fully seated in theslot, actuation member 314 is in a locked position. A twisting motion ofthe housing or the actuation member unlocks the pin and slot, so thatthe actuation member can be deployed.

FIGS. 8A-8B illustrate other examples of tab safety mechanisms, where inFIG. 8A a cantilevered push tab 320 is movable to displace a pin 322that locks an actuation member 324 in place. FIG. 8B shows a twist tabor snap tab 326 that interferes with movement of the actuation member328. Removing the twist tab by twisting until it breaks off releases thesafety mechanism and allows actuation of the applicator.

In a second embodiment, a safety mechanism in the form of a protectivecap is provided, to prevent inadvertent actuation of an applicatorcomprising a microneedle array. An example is provided in FIGS. 9A-9B,where cap 350 is shown in a closed position (FIG. 9A) and in an openposition (FIG. 9B). Cap 350 comprises a retaining member 352 and a cupmember 354 connected to the retaining member by a flexible bridge member356. Barbs or hooks extend from the retaining member, to fix the caponto an applicator, as depicted in FIG. 9B. The cup member shields anactuation member on the applicator, preventing inadvertent applicationof force to the actuation member, and consequential deployment of themicroneedle array.

FIGS. 10A-10B illustrate another embodiment of a cap type safetymechanism, where a peel cap 360 fits snugly about the outer periphery ofan applicator, preventing access to the actuation member of theapplicator. Removal of the peel cap exposes the actuation member,rendering it available for use.

In another embodiment, the applicator described herein is designed toprevent unintended actuation of the applicator and consequentialdeployment of the microneedle array in accord with the design depictedin FIGS. 11A-11B. FIG. 11A depicts an applicator 400 in a configurationprior to deployment or actuation by a user. FIG. 11B depicts the sameapplicator after deployment or actuation by a user. Applicator 400 iscomprised of a rigid housing 402 comprised of a first member 404 and asecond member 406. In other embodiment, the housing is semi-rigid,semi-flexible, or flexible. First and second members are configured toengage one another so as to fit together in a secure configuration, suchas by a snap-fit mechanism or an insertable lip/groove mechanism (seen,for example, in FIG. 12A). First member or upper housing member 404 hasa central opening 408 in which an actuating member 410 slidingly fits.Second member or skin contacting member 406 is hollow or open, toreceive the actuating member upon actuation of the applicator, as seenin FIG. 11B. Prior to actuation of the application (FIG. 11A), the planeof the top surface of actuating member, denoted by dashed line 412 inFIG. 11A, is co-planar or slightly under/lower than the plane of theuppermost edge of the first member 404 of housing 402, denoted by dashedline 414 in FIGS. 12A-12B, which are cross-sectional views of anexemplary applicator. In this configuration, the external, upper surfaceof the actuating member is co-planar with the uppermost surface of thehousing, so that the actuating member is nested into or recessed intothe housing prior to its actuation. After actuation of the actuatingmember, wherein the actuating member is deployed to a second position,the actuating member is depressed into the housing and the upper surfaceof the actuating member approaches a plane defined by an upper rim ofthe second housing member 406, denoted by dashed line 416 in FIGS.12A-12B. As can be appreciated, the design wherein the actuating memberis nested into the housing prior to actuation (e.g., the actuatingmember does not extend outward from the housing) prevents inadvertentdeployment of the applicator.

The internal components of an applicator wherein the actuating member'supper external surface is flush with the uppermost (proximal withrespect to the skin contacting surface of the housing) surface ofhousing can vary, and two embodiments are shown in FIGS. 12A-12B andFIGS. 13A-13B, wherein like elements with respect to FIGS. 11A-11B aregiven like numerical identifiers despite FIGS. 12A-12B and FIGS. 13A-13Bbeing different embodiments. In FIGS. 12A-12B, applicator 400 is shownin a side cross-sectional view. First member 404 of housing 402 has anupper rim 420 that defines an uppermost plane of the applicator, theupper plane denoted by the dashed line 414. Actuating member 410 ismovably positioned in the housing, movable between first and secondpositions, where in its first position the upper surface of theactuating member, denoted by the plane indicated by dashed line 412, isco-planar with the upper plane of the applicator or is slightly lowerthan the upper plane of the applicator, as seen in FIG. 12A. Uponapplication of a force, depicted by arrow 422, by a user, the actuatingmember travels to its second position, for deployment into the skin of auser of a microneedle array (not shown) positioned on a holding member424 engaged with the actuating member. In its second, deployed position,the upper surface of the actuating member approaches, contacts, ortravels beyond, a plane defined by an upper rim of the second housingmember 406, the plane denoted by dashed line 416.

With continuing reference to FIGS. 12A-12B, actuating member 410 travelsfrom its first to second positions along a plurality of guide fins, suchas fins 426, 428. A groove for each guide fin, such as groove 430, isdisposed in actuating member. Grooves or slots are similarly provided inthe first and second members of the housing, to secure each guide fin inthe applicator. The plurality of guide fins guide the plunger of theactuating member relative to the housing to maintain alignment duringactivation of the device. Each guide fin is dimensioned with sufficientthickness to avoid sharp edges, and the edges can be curved with aradius of curvature to ensure no sharp edging. It is also desirable thateach guide fin have a horizontal axis of symmetry that allows for itsinsertion into the housing in either direction.

FIGS. 13A-13B are cross-sectional side views of another embodiment ofthe applicator of FIGS. 11A-11B, wherein FIG. 13A shows the applicatorprior to activation and FIG. 13B shows the applicator after itsactivation. In this embodiment, the applicator prior to activation hasan actuating member 410 that is recessed within the housing, as evidentfrom the fact that the upper surface of the actuating member is below orunder the upper rim of the first housing member 404, as illustrated bythe respective dashed lines 412 (corresponding to the plane defined bythe upper surface of the actuating member) and 414 (corresponding to theplane defined by the plane defined by upper rim of the first housingmember). As seen in FIG. 13B, activation of the actuating member byapplication of a force moves the actuating member to its secondposition, wherein the upper surface of the actuating member is closer(relative to the upper surface of the actuating member in its firstposition) to the upper rim 407 of the second housing member 406, denotedby dashed line 416. The actuating member travels from its first tosecond positions along a plurality of guide posts, such as posts 432,434. The guide posts extend from the first member of the housing to thesecond member of the housing, and are affixed to the each member. Theouter circumference of the actuating member contacts each of the guideposts, which serve to guide the actuating member relative to the housingduring movement of the actuating member.

FIGS. 12A-12B and 13A-13B also illustrate the energy storage element 436positioned with the applicator. As discussed in detail above, the energystorage element moves from a first position to a second position uponapplication of a force by the actuating member. Movement from its firstto its second position occurs only upon application of a sufficientforce, and results in an inversion of the element. The element is stablein both its first and second positions in that it does not of its ownaccord move between the positions, but requires application of force tomove from its first to its second position, and from its second positionto its first position. In a preferred embodiment, the force required tomove the element from its second to its first position is less than theforce required to move the element from its first to its secondposition. Absent application of force, the element cannot return to itsfirst position subsequent to actuation of the device. Prior toactivation of the applicator, the energy storage element contacts thesecond housing member that is in contact with the skin, and afteractivation, the energy storage element is in contact with the firstmember of the housing (also referred to as an outer cover). Activationof the actuation member releases energy stored in the energy storageelement, the release energy acting on the microprojection holding memberin contact with the actuating member.

Methods of Use

In another aspect, a method for administering an active agent to asubject is provided. The method comprises providing a microprojectionarray in conjunction with any one of the applicators described herein,the microprojection array comprising an active agent. The agent isdelivered transdermally by actuation of the applicator, to deploy themicroprojection array into contact with the skin, or more generally amembrane or body surface, of a subject. The active agent to beadministered can be one or more of any of the active agents known in theart, and include the broad classes of compounds such as, by way ofillustration and not limitation: analeptic agents; analgesic agents;antiarthritic agents; anticancer agents, including antineoplastic drugs;anticholinergics; anticonvulsants; antidepressants; antidiabetic agents;antidiarrheals; antihelminthics; antihistamines; antihyperlipidemicagents; antihypertensive agents; anti-infective agents such asantibiotics, antifungal agents, antiviral agents and bacteriostatic andbactericidal compounds; antiinflammatory agents; antimigrainepreparations; antinauseants; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics; antispasmodics; antitubercular agents;antiulcer agents; anxiolytics; appetite suppressants; attention deficitdisorder and attention deficit hyperactivity disorder drugs;cardiovascular preparations including calcium channel blockers,antianginal agents, central nervous system agents, beta-blockers andantiarrhythmic agents; caustic agents; central nervous systemstimulants; cough and cold preparations, including decongestants;cytokines; diuretics; genetic materials; herbal remedies; hormonolytics;hypnotics; hypoglycemic agents; immunosuppressive agents; keratolyticagents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants;narcotic antagonists; nicotine; nutritional agents, such as vitamins,essential amino acids and fatty acids; ophthalmic drugs such asantiglaucoma agents; pain relieving agents such as anesthetic agents;parasympatholytics; peptide drugs; proteolytic enzymes;psychostimulants; respiratory drugs, including antiasthmatic agents;sedatives; steroids, including progestogens, estrogens, corticosteroids,androgens and anabolic agents; smoking cessation agents;sympathomimetics; tissue-healing enhancing agents; tranquilizers;vasodilators including general coronary, peripheral and cerebral;vessicants; and combinations thereof.

In preferred embodiments is a protein or a peptide. In anotherembodiment, the agent is a vaccine. Example 1 below detailsadministration of human parathyroid hormone to porcine skin in vitro.Examples 2-4 detail administration of human parathyroid hormone to humansubjects. Additional details of administration of human parathyroidhormone to human subjects using a microprojection array, includingdetailed pharmacokinetic analysis, are given in provisional applicationNo. 61/331,226, filed May 4, 2010; the entire contents of this co-filedapplication are incorporated by reference herein. Additional examples ofpeptides and proteins which may be used with microneedle arrays areoxytocin, vasopressin, adrenocorticotropic hormone (ACTH), epidermalgrowth factor (EGF), prolactin, luteinizing hormone, folliclestimulating hormone, luliberin or luteinizing hormone releasing hormone(LHRH), insulin, somatostatin, glucagon, interferon, gastrin,tetragastrin, pentagastrin, urogastrone, secretin, calcitonin,enkephalins, endorphins, kyotorphin, taftsin, thymopoietin, thymosin,thymostimulin, thymic humoral factor, serum thymic factor, tumornecrosis factor, colony stimulating factors, motilin, bombesin,dinorphin, neurotensin, cerulein, bradykinin, urokinase, kallikrein,substance P analogues and antagonists, angiotensin II, nerve growthfactor, blood coagulation factors VII and IX, lysozyme chloride, renin,bradykinin, tyrocidin, gramicidines, growth hormones, melanocytestimulating hormone, thyroid hormone releasing hormone, thyroidstimulating hormone, pancreozymin, cholecystokinin, human placentallactogen, human chorionic gonadotropin, protein synthesis stimulatingpeptide, gastric inhibitory peptide, vasoactive intestinal peptide,platelet derived growth factor, growth hormone releasing factor, bonemorphogenic protein, and synthetic analogues and modifications andpharmacologically active fragments thereof. Peptidyl drugs also includesynthetic analogs of LHRH, e.g., buserelin, deslorelin, fertirelin,goserelin, histrelin, leuprolide (leuprorelin), lutrelin, nafarelin,tryptorelin, and pharmacologically active salts thereof. Administrationof oligonucleotides are also contemplated, and include DNA and RNA,other naturally occurring oligonucleotides, unnatural oligonucleotides,and any combinations and/or fragments thereof. Therapeutic antibodiesinclude Orthoclone OKT3 (muromonab CD3), ReoPro (abciximab), Rituxan(rituximab), Zenapax (daclizumab), Remicade (infliximab), Simulect(basiliximab), Synagis (palivizumab), Herceptin (trastuzumab), Mylotarg(gemtuzumab ozogamicin), CroFab, DigiFab, Campath (alemtuzumab), andZevalin (ibritumomab tiuxetan).

It is to be understood that while the subject matter has been describedin conjunction with the preferred specific embodiments thereof, theforegoing description is intended to illustrate and not limiting inscope. Other aspects, advantages, and modifications will be apparent tothose skilled in the art to which the subject matter pertains.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties. However, where apatent, patent application, or publication containing expressdefinitions is incorporated by reference, those express definitionsshould be understood to apply to the incorporated patent, patentapplication, or publication in which they are found, and not to theremainder of the text of this application, in particular the claims ofthis application.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the subject matters described herein, and are not intendedto limiting in the scope of the subject matter. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. andpressure is at or near atmospheric.

Example 1 Comparative Testing of Applicators

Three slotted spring applicators designated B1, B2 and B3, similar tothose depicted in FIGS. 1A-1F, were compared with an applicatordesignated “A” of the type depicted in FIGS. 4A-4B for skin penetrationefficiency and ability to deliver hPTH(1-34) (human parathyroid hormone1-34 fragment, also referred to as teriparatide when producedrecombinantly). The applicators B1, B2 and B3 differed in the precisecharacteristics of the slotted spring energy-storing element (dimensionsand material). Applicator B1 was 0.012 inches thick stainless steel,Applicator B2 was 0.0155 inches thick and made of 17-7 stainless steel,and Applicator B3 was 0.0155 inches thick and made of 301 stainlesssteel. The B1 slotted springs had somewhat longer indentations from theoutside in comparison to the B2 and B3 slotted springs.

Microprojection arrays were fabricated from Dextran-70 and containinghPTH(1-34), as described in U.S. Publication No. 2008-0269685. Thesequence of hPTH(1-34) used was:

(SEQ ID NO: 1) H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH

The microneedles were 4-sided pyramids with spacing 200 μm, microneedleheight 250 μm, and array diameter 11 mm, with 2742 microneedles perarray.

Testing was done with porcine skin smoothed flat on a polyurethane foambacking. The apparent dose delivered was determined by analyzing theresidual amount of hPTH(1-34) in the arrays and on skin. Results areshown in the table.

Device Apparent Dose % Delivery Efficiency ID Rep# % SPE¹ μg Mean SD %Mean SD A Rep 1 94.3 32.4 32.0 0.6 86.4 85.2 1.7 Rep 2 98.9 31.5 84.0 B1Rep 1 83.3 18.9 23.0 5.7 50.4 61.3 15.1 Rep 2 90.4 17.4 46.4 Rep 3 96.926.7 71.2 Rep 4 93.7 28.9 77.1 B2 Rep 1 99.9 18.5 27.7 6.2 49.3 73.716.4 Rep 2 101.1 30.2 80.5 Rep 3 100 30.0 80.0 Rep 4 99.5 31.9 85.1 B3Rep 1 92.9 8.9 19.3 8.6 23.7 51.3 22.9 Rep 2 100.8 27.0 72.0 Rep 3 94.815.5 41.3 Rep 4 96.4 25.6 68.3 ¹SPE = skin penetration efficiency

Skin penetration efficiency (SPE) is estimated by counting the number ofholes in the microneedle-treated skin region relative to the number ofmicroneedles on the array used to treat the skin. It is believed thatcertain weaker results for SPE, such as the first replication of the B1applicator, could be due to a possible error installing the slottedspring upside down into the plastic housing.

Example 2 Preparation of a Two-Layer Microprojection Array containingHuman Parathyroid Hormone (hPTH(1-34))

A microprojection array containing a therapeutically effective amount ofhPTH(1-34) (32 μgrams) was prepared for use in a Phase I clinical studyas follows.

First, in describing generally the features of the microprojectionarray, the microprotrusions of the array can be characterized generallyas comprising a DIT (drug-in-tip) layer and a “backing” layer. The DITlayer includes hPTH(1-34) in a water-soluble matrix. The sequence ofhPTH(1-34) used is as follows:

(SEQ ID NO: 1) H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH

The tip of the microprojections is also referred to herein as the layerat the bottom-most portion of the tips or microprotrusions (i.e.,proximal to the skin when placed upon the skin), also referred to hereinas the “end portion” that is distal to the base of the array). The“backing” layer as referred to in certain of these examples, encompassesboth the upper portion of the microprotrusions proximal to the base ofthe array as well as the base itself, where the base is the portion ofthe array that supports the tips. The backing layer comprises abiocompatible, non-water soluble matrix. In the instant array device,the material in the upper portion of the microprotrusions is the same asthe base material itself, so that the non-water soluble matrixformulation is applied as a single layer to fill the mold atop the DITlayer.

The DIT layer of the microstructure array dissolves into the skin andcontains the components provided in Table 2-1. Acetate was thecounter-ion in the hPTH(1-34) drug substance.

TABLE 2-1 Composition of Drug-in-Tip Layer of hPTH(1-34) TDS % w/w (ofthe micro- Chemical Name Quantity Range structure Trade Name ofIngredient (μg/unit) (μg/unit) array) hPTH (1-34) human 32.0 25.6-38.412.8 Parathyroid hormone (1-34) Dextran 70 Dextran, 70,000 160.0128.0-192.0 58.6 Dalton molecular weight Sorbitol, N.F. Sorbitol 54.964.0-96.0 21.9 Histidine L-histidine 0.14 0.11-0.17 0.1 Histidine HClL-histidine 0.73 0.58-0.88 0.3 hydrochloride NA Acetate 2.5 2.0-3.0 1.0Total 250.27 100.0

The backing portion or layer of the array was composed ofpoly(DL-lactide-co-glycolide), 75:25, ester terminated (Tradename:LACTEL®).

The ingredients forming the tip portion of the formulation (i.e., theDIT formulation) were dissolved in water, cast, and dried in a siliconemold containing microstructure cavities to form the drug-in-tips (DIT)structures. The water insoluble, biocompatible polymer,poly(DL-lactide-co-glycolide), 75:25, was dissolved in acetonitrile toprovide the backing formulation which was then coated on top of the DITlayer in the silicone mold, and then dried. The solvent was removed fromthe backing (upper portion proximal to the base, and base) duringprocessing and was limited to a level below the amounts recommended inICH guidelines.

Example 3 Preparation of a Transdermal Delivery Device (TDS) containinga Microprojection Array containing Human Parathyroid Hormone(hPTH(1-34))

The final transdermal/microneedle delivery system product (sometimesabbreviated herein “TDS”) was assembled and contained themicroprojection array described above in Example 2. The product wasdesigned to deliver a systemic dose of hPTH (1-34) across the stratumcorneum barrier layer of the skin using an array of microstructures. Thefinal TDS product was formed by the integration of two components, aplunger-array assembly containing drug product and an applicatorassembly, where these two items were packaged separately and integratedat the clinical site (See Example 4 below for clinical data).

The microprojection array contained in the plunger-array assemblypossesses an 11 millimeter diameter of approximately 2700microstructures arranged in a hexagonal pattern. The plunger-arrayassembly consists of the microprojection array mounted to an arraysupport member, in this case, as plastic plunger with an adhesivelaminate. The plunger-array assembly was packaged inside a protectivecontainer and pouched in a dry nitrogen environment.

The applicator assembly includes a plastic shell or housing with skincontact adhesive and a release liner, an energy storage member (in thiscase, a metal spring) to provide the energy needed to accelerate theplunger-array assembly, and elements to hold these items together untilassembly at the clinic with the plunger-array assembly. This unit ispackaged inside a protective container and pouched.

The final assembled drug product consists of the plunger-array assemblywhich is inserted into the applicator assembly. The TDS is activated bycompressing the spring and then twisting the plunger to lock and holdthe compressed spring in place until use. When activated, the springdelivers the stored energy to the plunger causing it to accelerate andcontact the skin. Upon contact with the skin, the microstructurespenetrate past the stratum corneum, and the hPTH dissolves into the skinrapidly. Following actuation of the spring and delivery of hPTH, thedevice is removed and discarded. The applicator assembly andplunger-array assembly as well as the final assembled TDS productcorrespond to those shown in FIGS. 4A-4B.

Example 4 In-Vivo Study: Administration of Human Parathyroid Hormone,hPTH(1-34), Via a Microprojection Array Device in Healthy Human Subjects

An open label, single dose, sequence randomized, 3-way cross-over studywas carried out in sixteen healthy female volunteers to determine thepharmacokinetics (along with additional secondary endpoints) of 32 μghPTH(1-34) and 64 μg hPTH(1-34) (32 μg hPTH(1-34)×2) delivered using themicroneedle transdermal delivery system identified by the tradenameMicroCor®, described in Examples 2 and 3 relative to subcutaneouslyadministered (SC) hPTH (teriparatide) commercially available under thetradename FORTEO®, 20 μg. One subject was withdrawn after the firsttreatment due to difficulty in bleeds resulting from venous spasms. Theproduct described in Examples 2 and 3 is referred to in this examplegenerally as “MicroCor® hPTH(1-34)” or simply, “MicroCor®”.

Subjects received a single dose of 32 μg hPTH(1-34) or 64 μg hPTH(1-34)(32 μg×2) by applying the MicroCor® device to an abdominal site for 5minutes. Treatment with FORTEO® was accomplished by administration as asubcutaneous injection into the abdominal wall. Treatments wereseparated by a 48-hour washout period. The plasma sampling schedule wasas follows: pre-treatment, 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90,120, 180, 240, 300, 360 minutes, and 24 hours post-treatment. Vitalsigns were monitored pre-treatment, and at 15 and 30 minutes, and 1, 2,3, 4, 5, 6, 8, 10, 12, and 24 hours post-treatment. Adverse advents weremonitored throughout the study. Additional assessments included (i)measurement of anti-PTH antibodies prior to first treatment and 2 weeksfollowing last treatment, (ii) measurement of serum calcium,phosphorous, albumin, and protein at pre-treatment, and 1, 2, 3, 4, 5,6, and 24 hours post-treatment, as well as (iii) MicroCor® adhesion. Thefollowing tables summarize study results.

TABLE 4-1 Local Skin Tolerability MicroCor ® (N = 17; FORTEO ® SymptomsObservation 49 applications) (N = 16) Evidence of bleeding Yes 0 1(6.3%) No 49 (100%)  15 (93.7%) Discomfort at None  9 (18.4%) 10 (62.5%)application Mild 31 (61.2%)  5 (31.3%) Moderate 10 (20.4%) 1 (6.3%)Discomfort pre- None 26 (53.1%) N/A removal (MicroCor ® Mild 21 (42.9%)only) Moderate 2 (4.1%) Discomfort at None 44 (89.8%) N/A removal(MicroCor ® Mild  5 (10.2%) only)

TABLE 4-2 Pharmacokinetic Results MicroCor ® MicroCor ® Parameter 32 μg64 μg FORTEO ® AUC/Dose 220 (n = 15) 229 (n = 16) 429 (n = 16) (pg*min/mL*mcg) C_(max) (pg/mL) 180 (n = 16) 336 (n = 16) 85 (n = 16)T_(max) (minutes)  8.1 (n = 16)  7.4 (n = 16) 26.2 (n = 16)  T_(1/2)(minutes) 37.1 (n = 16)  52.0 (n = 16)  52 (n = 16) Time to reach 50%~20 ~20 ~90 minutes of Cmax (plasma normalized), minutes

Application of hPTH with the MicroCor device demonstrated good skintolerability. Skin effects were transient and well-tolerated, with mildto moderate erythema observed.

In terms of general safety, all treatment regimes were well-tolerated.No significant adverse events nor unexpected adverse events occurred. Infact, there was no difference in the overall treatment-related adverseevents between application of the hPTH via the MicroCor® device and theForteo®-based treatment. No significant changes were observed in serumcalcium, and no anti-PTH antibodies were detected—again, furtherdemonstrating the overall safety of MicroCor®-based treatment in humansubjects.

As can be seen from the data summarized in Table 4-2, relative to theForteo® product, the MicroCor® delivery system exhibits rapidpharmacokinetic properties such as a shorter T_(max), a higher C_(max),and a shorter elimination half life, T_(1/2), as compared to asubcutaneous injection of the agent. Absorption of hPTH (1-34) occurredmore rapidly with the MicroCor® delivery system relative to the Forteo®product, as illustrated by the higher dose-normalized C_(max) value andthe faster T_(max) values for both MicroCor® treatments. The half-lifebased upon administration via the MicroCor®device as also shorter thanwith Forteo®. Moreover, application using the MicroCor® device was moreeffective in achieving the desired pulsatile delivery profile ofhPTH(1-34) (i.e., rapid on set and rapid offset after reaching Cmax).

The MicroCor®-based delivery results in faster elimination of drug.Based upon a plot of plasma concentration (normalized) versus time, itcan be seen that the time to reach 50% of Cmax for the MicroCor®-basedtreatments was approximately 20 minutes for both the 32 and 64 microgramtreatments (i.e., based upon the time to reach a normalized plasmaconcentration of 0.5). In contrast, the time to reach 50% of Cmax forthe Forteo®-based treatment was approximately 1.5 hours (90 minutes),based upon time post-administration. Thus, the time to reach 50% of Cmaxfor the MicroCor®-based treatments was approximately 4.5 times less thanthat observed for subcutaneously injected PTH (Forteo®) indicatingnotably faster elimination of drug when administered transdermally froma microneedly array as in the MicroCor® system.

Finally, based upon a residual analysis of the PTH content of theMicroCor® delivery system following delivery of drug, it was determinedthat, on average, about 85% of drug was delivered from the device (i.e.,85% delivery efficiency).

It is claimed:
 1. An applicator for a microprojection array, comprising:a housing with an opening; an actuating member having an externalsurface for application of a force, where the actuating member fitsslidably in the housing opening between a first position and a secondposition; a push member comprising a microprojection array attached to adistal surface of a proximal end of the push member, the push memberhaving a first position and a second position; an energy-storing elementhaving a first configuration and a second configuration, theenergy-storing element being positioned between a lower surface of thehousing and the proximal end of the push member; wherein the push memberis retained in the first position until application of force to theactuating member moves the actuating member from the first position tothe second position, thereby to release the push member andcorresponding release of the energy-storing element.
 2. The applicatorof claim 1, wherein the energy-storing element is in mechanicalcommunication with the push member when the energy-storing element is inits first configuration.
 3. The applicator of claim 1, wherein theactuator member extends from an upper surface of the housing when in thefirst position.
 4. The applicator of claim 1, wherein the distal surfaceof the push member extends beyond a distal end of the housing when thepush member is in the second position.
 5. The applicator of claim 1, thehousing comprising at least one projection for restraining the pushmember in the first configuration.
 6. The applicator of claim 1, whereinthe energy-storing element is selected from the group consisting of aspring and an elastic element.
 7. The applicator of claim 1, wherein theenergy-storing element is formed of a material selected from metals,alloys, and plastics.
 8. The applicator of claim 1, further comprising asafety mechanism to prevent movement of the actuation member in adirection that releases the push member.
 9. The applicator of claim 1,wherein the microprojection array comprises at least one active agent.10. A method of administering an active agent to a patient in need ofthat agent, comprising: placing an applicator according to claim 1 on abody surface of a patient, wherein the microprojection array comprisesat least one active agent; applying a force to the external surface ofthe actuating member to move the actuating member from the firstposition to the second position and thereby release the push member fromthe first position to the second position, thereby to insert at least aportion of the microprojection array in to the body surface; therebyadministering the at least one active agent.
 11. The method of claim 10,further comprising detaching the microprojection array from the pushmember such that the microprojection array remains inserted at the bodysurface site.